This invention provides a stable, injectable aqueous solution of vinca dimer salts, suitable for intravenuous injection for the treatment of neoplastic diseases, particularly leukemias, in humans.
Certain vinca alkaloids, being dimeric indole-dihydroindole compounds, have been used for some time in chemotherapy as oncolytic drugs, particularly for the treatment of leukemias. Among those so-called vinca dimers, there might be mentioned especially vincristine, vinblastine and vindesine (an amide derivative of vinblastine). The treatment consists of intravenous administration of pharmaceutically acceptable salts of the vinca dimers, in most cases the sulfate salt, to patients suffering from neoplastic diseases. Owing to the toxic properties of the vinca dimer salts, these must be administered in carefully accurate dosages.
In past years, vinca dimer salts for chemotherapy, and particularly vincristine sulfate, were marketed in sealed vials containing a desired dosage of lyophilized vinca dimer salt, from which an aqueous solution for injection had to be reconsituted in situ. Such a procedure involves many drawbacks as compared to the use of ready made injectable solutions, the main drawbacks being: errors in concentration of the vinca dimer salt owing to improper reconsitution of the lyophilized product; risk of contact with the toxic drug to the medical personnel preparing the injectable solutions; and waste of these very expensive drugs resulting from the need to discard the excesses of such reconstituted injectable solutions, which can be stored for comparatively short periods only (the recommended life of a reconsituted vincristine sulfate solution is 14 days at refrigerator temperatures, whereafter the solution becomes hazy and a precipitate forms therein).
Stable, ready-to-use aqueous solutions of vinca dimer salts were disclosed in Israel Patent Specification No. 69203 to Eli Lilly & Company and in the corresponding U.S. Pat. No. 4,619,935. In accordance with said Israel Patent the formulation comprises, in addition to a pharmaceutically acceptable vinca dimer salt, a polyol, an acetate buffer to maintain the pH of the solution between 3.0 and 5.0 and a preservative. As contrasted thereto, the U.S. Pat. No. 4,619,935.is restricted to formulations comprising an aqueous solution of about 1-2 mg/ml of a vincristine salt, about 10-100 mg/ml of a polyol selected from mannitol, sorbitol and sucrose, an acetate buffer as in the corresponding Israel patent and about 1-2 mg/ml of a preservative selected from methyl paraben and propyl paraben, singly or in combination. The formulations of this U.S. patent thus roughly correspond to the preferred embodiments described and claimed in Israel patent No. 69203. Both said Israel and U.S. patents state (in Example 4 therein) that the vincristine sulfate formulations disclosed therein "have remained physically and chemically acceptable for pharmaceutical use for periods up to 1 year at 5.degree. C.". However, the stability test results given in the same Example 4 of these patents merely showed that said formulations "maintained 94-99% of their initial concentration after storage at 5.degree. C. for about 9 months".